PROJECT SUMMARY Abnormal activity patterns in specific neuron networks may underlie dysfunction in many brain diseases. It is therefore a goal of translational research to manipulate the activity of specific brain pathways in an effort to restore normal function. Current clinical neuromodulation methods (such as deep brain stimulation) are relatively non-specific, and can lead to significant side effects. Novel genetically based neuromodulation techniques have made it possible to more precisely target specific neuron populations. Among these, chemogenetic techniques have gained attention because of their high translational potential. These methods involve the use of engineered receptors that are introduced into specific neuron types using genetic manipulations. The receptors will not be activated by endogenous neurotransmitters, but only by exogenously applied compounds. Thus, a systemically administered drug can elicit specific actions in genetically targeted neuron populations. While widely used in rodents, chemogenetic methods in primates remains in its infancy. We are interested in the use of chemogenetic tools to control ligand-gated ion channels (LGICs) in primates. These channels can directly influence the electrical properties of neurons and increase or decrease the neuronal activity depending on the ion channel. A recently developed subtype of LGICs, termed ?pharmacologically selective actuator molecules? (PSAMs), is based on nicotinic receptors which are engineered to not recognize their endogenous activator, acetylcholine, but to be selectively activated by very small doses of the clinically approved drug varenicline. The fact that the PSAM approach re-purposes a clinically used drug makes it highly attractive for translation into therapy for human diseases. However, PSAMs have not yet been used in primates (human or non-human). It is therefore essential to examine the expression and function of these receptors in monkeys. In this project, we plan to study whether PSAMs can be used in monkeys to manipulate neuron activities and behavior. It is our long-term goal to test the potential of PSAMs as an antiparkinsonian treatment. In the proposed experiments, we will express PSAMs in the internal pallidum (GPi) of monkeys using viral vectors. We have chosen GPi as a target because GPi activity is abnormal in various movement disorders, including Parkinson?s disease (PD), and manipulation of GPi activity (such as pallidotomy procedures) has antiparkinsonian properties. Once the (inhibitory) PSAMs are expressed in GPi, we will systemically administer varenicline, expecting to induce a reduction of the activity of GPi neurons and slow movement. The expression of PSAMs will be verified by in vivo PET imaging, as well as post-mortem histology. Data generated by this project will be used for a subsequent R01 proposal in which we will examine the effects of PSAM-mediated inactivation of GPi in MPTP-treated parkinsonian monkeys. If we find that this technique has antiparkinsonian properties without inducing adverse effects, it could be developed into a new therapy for treating PD symptoms with fewer side effects than the currently available methods.